Levorotatory [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid, also known by the generic name of levocetirizine, has proven useful as a therapeutic agent for the treatment of allergic disease.
Levocetirizine and its salts including its dihydrochloride are known and are effective in the treatment of allergies, including but not limited to, chronic and acute allergic rhinitis, allergic conjunctivitis, pruritus, urticaria and the like. Levocetirizine belongs to the second generation of H1 histamine receptor antagonists, which are believed to offer significant advantages over first generation compounds. Studies have shown that levocetirizine provides safe and effective symptomatic relief of seasonal allergies. Levocetirizine is used also for treating chronic idiopathic urticaria.
GB 2,225,321 describes a process for the preparation of cetirizine in the levorotatory form, dextrorotatory form or a mixture thereof comprising the hydrolysis of enantiomerically pure [2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetonitrile. Hydrolysis takes place in aqueous, alcoholic or aqueous-alcoholic medium by a base or by an acid; the acid thus obtained is converted to its dihydrochloride. Optically active starting material 1-[(4-chlorophenyl)phenylmethyl]piperazine is obtained by resolution of the corresponding racemic compound, preferably by conversion to its diastereoisomeric salt with tartaric acid. The yield of resolution is rather low, namely only 12.7%. The obtained optically active intermediate is further converted with chloroethoxyacetonitrile in 69% yield.
EP 0 617 028 and EP 0 955 295 disclose a process for the preparation of optically active 1-[(4-chlorophenyl)phenylmethyl]piperazine and its conversion to cetirizine in the levorotatory form or dextrorotatory form or to derivative thereof. The process for the preparation is shown in the following scheme:

The drawback of the disclosed reaction is that it requires protection of N,N-bis(2-haloethyl)amine, and consequently deprotection of the intermediate obtained.
Preparation of Cetirizine in its Levorotatory Form Proceeds in most known syntheses from enantiomerically pure 1-[(4-chlorophenyl)phenylmethyl]piperazine. Consequently it appears to be very desirable to provide new routes to prepare the enantiomers thereof with improved optical purity and good yields.
Polymorphic form I of crystalline levorotatory dihydrochloride salt of cetirizine and amorphous form thereof are disclosed in WO 2004/050647 and WO 2004/065360. Crystalline form is prepared by crystallization from ketone-containing solvent, such as acetone, methyl ethyl ketone, dimethylketone, 2-pentanone and mixtures thereof. Amorphous form was prepared by solvent evaporation.
There still exists a need for an efficient synthesis of levocetirizine, new intermediates used in the process, suitable for large-scale production.